EP2365970B1 - Pyridazinones et leur utilisation comme inhibiteurs btk - Google Patents

Pyridazinones et leur utilisation comme inhibiteurs btk Download PDF

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EP2365970B1
EP2365970B1 EP09752681.8A EP09752681A EP2365970B1 EP 2365970 B1 EP2365970 B1 EP 2365970B1 EP 09752681 A EP09752681 A EP 09752681A EP 2365970 B1 EP2365970 B1 EP 2365970B1
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methyl
oxo
dihydropyridazin
amino
carboxamide
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English (en)
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EP2365970A1 (fr
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Antonio J. Barbosa, Jr.
Peter A. Blomgren
Kevin S. Currie
Seung H. Lee
Jeffrey E. Kropf
Scott A. Mitchell
Daniel Ortwine
William M. Rennells
Aaron C. Schmitt
Jianjun Xu
Wendy B. Young
Zhongdong Zhao
Pavel E. Zhichkin
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Genentech Inc
Gilead Connecticut Inc
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Genentech Inc
Gilead Connecticut Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Bruton's Tyrosine Kinase (Btk) is a member of the Tee family of tyrosine kinases, and is a regulator of early B-cell development as well as mature B-cell activation, signaling, and survival.
  • B-cell signaling through the B-cell receptor can lead to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell.
  • the magnitude and duration of BCR signals must be precisely regulated.
  • Aberrant BCR-mediated signaling can cause disregulated B-cell activation and/or the formation of pathogenic autoantibodies leading to multiple autoimmune and/or inflammatory diseases.
  • Mutation of Btk in humans results in X-linked agammaglobulinaemia (XLA). This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T-cell-independent immune responses and marked attenuation of the sustained calcium sign upon BCR stimulation.
  • XLA X-linked agammaglobulinaemia
  • Btk-deficient mice can also be resistant to developing collagen-induced arthritis and can be less susceptible to Staphylococcus-induced arthritis.
  • B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases.
  • Protein-based therapeutics such as Rituxan
  • Btk Because of Btk's role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (such as autoantibody production).
  • Btk is also expressed in osteoclasts, mast cells and monocytes and has been shown to be important for the function of these cells, For example, Btk deficiency in mice is associated with impaired IgE-mediated mast cell activation (marked diminution of TNF-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes.
  • inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases such as: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, and asthma.
  • Btk has been reported to play a role in apoptosis; thus, inhibition of Btk activity can be useful for cancer, as well as the treatment of B-cell lymphoma and leukemia.
  • the inhibition of Btk activity can be useful for the treatment of bone disorders such as osteoporosis.
  • compositions comprising a compound of any one of Formulae I, III-a, III-b, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, wherein the composition is formulated in a form chosen from injectable fluids, aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmic solutions, and transdermal patches.
  • a packaged pharmaceutical composition comprising a pharmaceutical composition as described above; and instructions for using the composition to treat a patient suffering from a disease responsive to inhibition of Btk activity.
  • a compound of any one of Formulae I, III-a, III-b for use in the treatment of a patient suffering from a disease responsive to inhibition of Btk activity.
  • a compound of any one of Formulae I, III-a, III-b for use in the treatment of a patient suffering from a disease responsive to inhibition of Btk activity, wherein the patient has a disease chosen from includes allergic disorders, including but not limited to eczema, allergic rhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) and food allergies, and other atopic conditions; autoimmune and/or inflammatory diseases, including but not limited to psoriasis, Crohn's disease, irritable bowel syndrome, Sjogren's disease, tissue graft rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitides), autoimmune hemolytic and thrombocytopenic states, Goodpasture'
  • Described herein is also a method for increasing sensitivity of cancer cells to chemotherapy, comprising administering to a patient undergoing chemotherapy with a chemotherapeutic agent an amount of a compound of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b, sufficient to increase the sensitivity of cancer cells to the chemotherapeutic agent.
  • Described herein is also a method of reducing medication error and enhancing therapeutic compliance of a patient being treated for a disease responsive to inhibition of Btk activity, the method comprising providing a packaged pharmaceutical preparation described herein wherein the instructions additionally include contraindication and adverse reaction information pertaining to the packaged pharmaceutical composition.
  • Described herein is also a method for inhibiting ATP hydrolysis, the method comprising contacting cells expressing Btk with a compound of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b in an amount sufficient to detectably decrease the level of ATP hydrolysis in vitro.
  • Described herein is also a method for determining the presence of Btk in a sample, comprising contacting the sample with a compound of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.
  • Described herein is also a method for inhibiting B-cell activity comprising contacting cells expressing Btk with a compound of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b in an amount sufficient to detectably decrease B-cell activity in vitro.
  • alkyl encompasses straight chain and branched hydrocarbon chain having the indicated number of carbon atoms.
  • C 1 -C 6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like.
  • butyl is meant to include n-butyl, sec-butyl, isobutyl and t-butyl;
  • propyl includes n-propyl and isopropyl.
  • cycloalkyl indicates a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to 7 ring carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as well as bridged and caged saturated ring groups such as norbornane.
  • alkoxy is meant an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like.
  • Alkoxy groups will usually have from 1 to 6 carbon atoms attached through the oxygen bridge.
  • “Lower alkoxy” refers to alkoxy groups having one to four carbons.
  • halo includes fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • Haloalkyl indicates alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • heteroaryl encompasses:
  • heteroarylalkyl heteroaryl and alkyle are as defined herein, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, pyridylmethyl, thiophenylmethyl, and (pyrrolyl)1-ethyl.
  • heterocycloalkyl is meant a monocyclic or bicyclic non-aromatic ring, usually with 3 to 14 ring atoms, containing at least 2 carbon atoms in addition to 1-5 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5-piperzinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (heteroaryl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • modulation refers to a change in kinase activity as a direct or indirect response to the presence of compounds described herein, relative to the activity of the kinase in the absence of the compound.
  • the change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the kinase, or due to the interaction of the compound with one or more other factors that in turn affect kinase activity.
  • the presence of the compound may, for example, increase or decrease kinase activity by directly binding to the kinase, by causing (directly or indirectly) another factor to increase or decrease the kinase activity, or by (directly or indirectly) increasing or decreasing the amount of kinase present in the cell or organism.
  • Compounds of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b include, but are not limited to, optical isomers of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds.
  • chemical entities of the present invention include all tautomeric forms of the compound.
  • Compounds also include crystal forms including polymorphs and clathrates.
  • the present invention includes compounds of Formulae I, III-a, III-b, as defined in the claims and all pharmaceutically acceptable forms thereof.
  • Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, and mixtures thereof.
  • the compounds described herein are in the form of pharmaceutically acceptable salts.
  • the compounds of this invention remain part of this invention even when they are in the form of chemical association with other chemical entities in the manner of a chelate or a non-covalent complex.
  • the terms "compound” and "chemical entity” are used interchangeably herein.
  • “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH 2 ) n -COOH where n is 0-4, and like salts.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • prodrugs for example ester or amide derivatives of the compounds of any one Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b.
  • prodrugs includes any compounds that become compounds of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b when administered to a patient, e.g., upon metabolic processing of the prodrug.
  • prodrugs include, but are not limited to, acetate, formate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b.
  • solvate refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
  • chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
  • a metal ion include Ca ++ and Mg ++ .
  • non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • hydrogen bond refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor).
  • Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry ( G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960 ; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp. 320-326 (1984 )).
  • an “active agent” is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • an active agent may be an anti-cancer therapeutic.
  • a therapeutically effective amount of a compound of this invention means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease e.g., a therapeutically effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of Btk activity.
  • a therapeutically effective amount is an amount sufficient to reduce cancer symptoms, the symptoms of bone disorders, the symptoms of an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction.
  • a therapeutically effective amount is an amount sufficient to decrease the number of detectable cancerous cells in an organism, detectably slow, or stop the growth of a cancerous tumor.
  • a therapeutically effective amount is an amount sufficient to shrink a cancerous tumor. In certain circumstances a patient suffering from cancer may not present symptoms of being affected. In some embodiments, a therapeutically effective amount of a compound/chemical entity is an amount sufficient to prevent a significant increase or significantly reduce the detectable level of cancerous cells or cancer markers in the patient's blood, serum, or tissues. In methods described herein for treating allergic disorders and/or autoimmune and/or inflammatory diseases and/or acute inflammatory reactions, a therapeutically effective amount may also be an amount sufficient, when administered to a patient, to detectably slow progression of the disease, or prevent the patient to whom the compound/chemical entity is given from presenting symptoms of the allergic disorders and/or autoimmune and/or inflammatory disease, and/or acute inflammatory response.
  • a therapeutically effective amount may also be an amount sufficient to produce a detectable decrease in the amount of a marker protein or cell type in the patient's blood or serum.
  • a therapeutically effective amount is an amount of a compound/chemical entity described herein sufficient to significantly decrease the activity of B-cells.
  • a therapeutically effective amount is an amount of a compound of any one of Formulae I, III-a, III-b, sufficient to significantly decrease the number of B-cells.
  • a therapeutically effective amount is an amount of a compound of any one of Formulae I, III-a, III-b, sufficient to decrease the level of anti- acetylcholine receptor antibody in a patient's blood with the disease myasthenia gravis.
  • inhibiting indicates a significant decrease in the baseline activity of a biological activity or process.
  • “Inhibition of Btk activity” refers to a decrease in Btk activity as a direct or indirect response to the presence of a compound of any one of described, but not claimed formula II-a, described, but not claimed formula II-b, Formulae I, III-a, III-b, described, but not claimed formula IV-a and described, but not claimed formula IV-b, relative to the activity of Btk in the absence of such compound.
  • the decrease in activity may be due to the direct interaction of the compound with Btk, or due to the interaction of such compound with one or more other factors that in turn affect Btk activity.
  • the presence of the compound may decrease Btk activity by directly binding to the Btk, by causing (directly or indirectly) another factor to decrease Btk activity, or by (directly or indirectly) decreasing the amount of Btk present in the cell or organism.
  • Inhibition of Btk activity also refers to observable inhibition of Btk activity in a standard biochemical assay for Btk activity, such as the ATP hydrolysis assay described below.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to micromolar.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to less than 25 nanomolar.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to 5 nanomolar.
  • “Inhibition of B-cell activity” refers to a decrease in B-cell activity as a direct or indirect response to the presence of a compound of any one of Formulae I, described, but not claimed formula II-a, described, but not claimed formula II-b, III-a, III-b, described, but not claimed formula IV-a and described, but not claimed formula IV-b, relative to the activity of B-cells in the absence of such compound.
  • the decrease in activity may be due to the direct interaction of the compound with Btk or with one or more other factors that in turn affect B-cell activity.
  • Inhibition of B-cell activity also refers to observable inhibition of CD86 expression in a standard assay such as the assay described below.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to 10 micromolar.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to less than 0.5 micromolar.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to 100 nanomolar.
  • B cell activity also includes activation, redistribution, reorganization, or capping of one or more various B cell membrane receptors, e.g., CD40, CD86, and Toll-like receptors TLRs (in particular TLR4), or membrane-bound immunoglobulins, e.g, IgM, IgG, and IgD. Most B cells also have membrane receptors for Fc portion of IgG in the form of either antigen-antibody complexes or aggregated IgG. B cells also carry membrane receptors for the activated components of complement, e.g., C3b, C3d, C4, and Clq. These various membrane receptors and membrane-bound immunoglobulins have membrane mobility and can undergo redistribution and capping that can initiate signal transduction.
  • B cell membrane receptors e.g., CD40, CD86, and Toll-like receptors TLRs (in particular TLR4)
  • membrane-bound immunoglobulins e.g, IgM, IgG, and I
  • B cell activity also includes the synthesis or production of antibodies or immunoglobulins.
  • Immunoglobulins are synthesized by the B cell series and have common structural features and structural units. Five immunoglobulin classes, i.e., IgG, IgA, IgM, IgD, and IgE, are recognized on the basis of structural differences of their heavy chains including the amino acid sequence and length of the polypeptide chain.
  • Antibodies to a given antigen may be detected in all or several classes of immunoglobulins or may be restricted to a single class or subclass of immunoglobulin.
  • Autoantibodies or autoimmune antibodies may likewise belong to one or several classes of immunoglobulins. For example, rheumatoid factors (antibodies to IgG) are most often recognized as an IgM imnnunoglobulin, but can also IgG or IgA.
  • B cell activity also is intended to include a series of events leading to B cell clonal expansion (proliferation) from precursor B lymphocytes and differentiation into antibody-synthesizing plasma cells which takes place in conjunction with antigen-binding and with cytokine signals from other cells.
  • Inhibition of B-cell proliferation refers to inhibition of proliferation of abnormal B-cells, such as cancerous B-cells, e.g. lymphoma B-cells and/ or inhibition of normal, non-diseased B-cells.
  • the term “inhibition of B-cell proliferation” indicates no increase or any significant decrease in the number of B-cells, either in vitro or in vivo.
  • an inhibition of B-cell proliferation in vitro would be any significant decrease in the number of B-cells in an in vitro sample contacted with a compound of any one of Formulae I, III-a, III-b, described, but not claimed formula II-a, described, but not claimed formula II-b, described, but not claimed formula IV-a and described, but not claimed formula IV-b, as compared to a matched sample not contacted with such compound.
  • Inhibition of B-cell proliferation also refers to observable inhibition of B-cell proliferation in a standard thymidine incorporation assay for B-cell proliferation, such as the assay described herein.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to 10 micromolar.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to less than 500 nanomolar.
  • a compound of any one of Formulae I, III-a, III-b has an IC 50 value less than or equal to 50 nanomolar.
  • Allergic disorder refers to acquired hypersensitivity to a substance (allergen). Allergic conditions include eczema, allergic rhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) and food allergies, and other atopic conditions.
  • Asthma refers to a disorder of the respiratory system characterized by inflammation, narrowing of the airways and increased reactivity of the airways to inhaled agents. Asthma is frequently, although not exclusively associated with atopic or allergic symptoms.
  • significant is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • a “disease responsive to inhibition of Btk activity” is a disease in which inhibiting Btk kinase provides a therapeutic benefit such as an amelioration of symptoms, decrease in disease progression, prevention or delay of disease onset, or inhibition of aberrant activity of certain cell-types (monocytes, osteoclasts, B-cells, mast cells, myeloid cells, basophils, macrophages, neutrophils, and dendritic cells).
  • a “disease responsive to inhibition of Btk activity” is a disease in which inhibiting Btk kinase provides a therapeutic benefit such as an amelioration of symptoms, decrease in disease progression, prevention or delay of disease onset, or inhibition of aberrant activity of certain cell-types (monocytes, osteoclasts, B-cells, mast cells, myeloid cells, basophils, macrophages, neutrophils, and dendritic cells).
  • Treatment or treating means any treatment of a disease in a patient, including:
  • Prevent or preventing a disease means causing the clinical symptoms of the disease not to develop.
  • Patient refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment.
  • the subject-matter of the invention as defined in the claims can be useful in both human therapy and veterinary applications.
  • the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is chosen from cats and dogs.
  • the compounds of the present invention are of Formula I wherein:
  • the compounds of the present invention are of Formula I-1 wherein:
  • R 3 is H. In certain embodiments, R 3 is CH 3 .
  • ring A is
  • X is CR 6 .
  • X is N.
  • Y is CR 7 .
  • Y is N.
  • Z is CR 8 .
  • Z is N.
  • the compounds of the present invention are of Formula III-a or III-b, wherein ring A is: wherein X, Y and Z can be independently N or X can be CR 6 , Y can be CR 7 and/or Z can be CR 8 , for example the compounds of Formulae III-a or III-b:
  • R 5 is H.
  • R 5 is F.
  • R 7 is chosen from H, F or CH 3 . In certain embodiments, R 7 is F. In certain embodiments, R 7 is H. In certain embodiments, R 7 is CH 3 .
  • R 8 is H.
  • R 1 is chosen from:
  • R 1 is or
  • R 2 is H, CH 3 or CH 2 OH. In certain embodiments, R 2 is H or CH 3 . In certain embodiments, R 2 is H. In certain embodiments, R 2 is - (CH 2 ) 3 N(CH 3 ) 2 . In certain embodiments, R 2 is OH. In certain embodiments, R 2 is CH 3 . In certain embodiments, R 2 is CH 2 OH. In certain embodiments, ring B is or optionally substituted by 1 to 3 R 4 moieties;
  • ring B with (R 4 ) 1-3 is: In certain embodiments, ring B with (R 4 ) 1-3 is wherein R 4 is CH 3 or CD 3 .
  • ring B with (R 4 ) 1-3 is: In certain embodiments, ring B with (R 4 ) 1-3 is wherein R 4 is CH 3 .
  • ring B with (R 4 ) 1-3 is: wherein R 4 is H, CH 3 , or CD 3 .
  • R 4 is H, -R a , -NR b R c , OR b , or COR b . In certain embodiments, R 4 is H, -R a , or -NR b R c . In certain embodiments, R a is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocloalkyl is optionally substituted with one to three R 11 groups.
  • R a is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocloalkyl is optionally substituted with one to three R 11 groups selected from C 1 -C 4 alkyl, -OH, heterocycloalkyl (optionally substituted with one to three R 12 groups), -OC 1 -C 4 alkyl, -O-heterocycloalkyl, oxo, halo, -NH 2 , -NH(C 1 -C 4 alkyl optionally substituted with one to three R 12 groups), -N(C 1 -C 4 alkyl optionally substituted with one to three R 12 groups) 2 , and -NH-heterocycloalkyl.
  • R a is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocloalkyl is optionally substituted with one to three R 11 groups selected from C 1 -C 4 alkyl, -OH, heterocycloalkyl (optionally substituted with one to three R 12 groups), -OC 1 -C 4 alkyl, -O-heterocycloalkyl, oxo, halo, -NH 2 , -NH(C 1 -C 4 alkyl optionally substituted with one to three R 12 groups), -N(C 1 -C 4 alkyl optionally substituted with one to three R 12 groups) 2 , -NH-heterocycloalkyl, wherein each R 12 is independently selected from OH, F, NH 2 , NHCH 3 , N(CH 3 ) 2 , and CH 3 .
  • R a is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocloalkyl is optionally substituted with one to three R 11 groups selected from C 1 -C 4 alkyl, -OH, heterocycloalkyl, -OC 1 -C 4 alkyl, O-heterocycloalkyl, or oxo.
  • R b is H, heterocycloalkyl, or C 1 -C 6 alkyl optionally substituted with one to three R 11 groups and R c is H or C 1 -C 4 alkyl.
  • R b is H, heterocycloalkyl, or C 1 -C 6 alkyl optionally substituted one to two R 11 groups independently selected from OH, NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 and heterocycloalkyl; and R c is H or C 1 -C 4 alkyl.
  • R b is C 1 -C 6 alkyl and R c is C 1 -C 4 alkyl.
  • R 4 is H, CH 3 , CH 2 CH 3 , t-butyl, CF 3 , -C(OH)(CH 3 ) 2 , - CH(OH)CH 3 , -CH 2 NH(CH 2 ) 2 O, -CH 2 NH(CH 2 )F, -CH 2 NHCH 3 , -CH 2 N(CH3) 2 , - CH 2 NHCH 2 CF 3 , -CH 2 OH, -CH 2 NH 2 , -OCH 3 , NH 2 , -N(CH 3 )(CH 2 ) 2 NMe 2 , - N(CH 3 )(CH 2 ) 2 OH, -N(CH 3 )(CH 2 ) 2 NH 2 , -CH(OH)C(O)N(CH 3 ) 2 , -CH 2 CHF 2 , -(CH 2 )
  • R 4 is H, CH 3 , CH 2 CH 3 , t-butyl, CF 3 , -C(OH)(CH 3 ) 2 , - CH(OH)CH 3 , -CH 2 NH(CH 2 ) 2 OH, -CH 2 NH(CH 2 )F, -CH 2 NIICH 3 , -CH 2 N(CH3) 2 , - CH 2 NHCH 2 CF 3 , -CH 2 OH, -CH 2 NH 2 , -OCH 3 , NH 2 , -N(CH 3 )(CH 2 ) 2 NMe 2 , - N(CH 3 )(CH 2 ) 2 OH, -N(CH 3 )(CH 2 ) 2 NH 2 , -CH(OH)C(O)N(CH 3 ) 2 NH 2 , -CH(OH)C(O)N(CH 3 ) 2 , -C(O)C(O)N(CH 3 )
  • each R 13 is independently H, F, O-t-butyl, t-butyl, or methyl.
  • R 1 contains a thiophene ring fused to a 5, 6, 7 or 8 membered ring as shown herein. In certain embodiments, R 1 contains a phenylene or benzo ring as shown herein.
  • the compound of the present invention is chosen from N-(3- ⁇ 5-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl ⁇ -2,6-difluorophenyl)thieno[3,2-b]pyridine-2-carboxamide; N-(2-fluoro-5- ⁇ 5-[(5-methyl-1,2-oxazol-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl ⁇ phenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide; N- ⁇ 2-fluoro-5-[6-oxo-5-(pyrimidin-ylamino)-1,6-dihydropyridazin-3-yl]phenyl ⁇ -4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide
  • the compound of Formula I is chosen from: Structure Name 4-hydroxy-N-(2-(hydroxymethyl)-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 5-tert-butyl-N-(2-(hydroxymethyl)-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)pyrazine-2-carboxamide 4-hydroxy-N-(2-(hydroxymethyl)-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-
  • the present compounds described herein are potent inhibitors of Btk. While not being bound by any theory, certain compounds have improved properties in the form of greater efficacy (as measured by, for example, the inhibition of Btk in whole blood and the inhibition of B-cell activation in mice).
  • compounds of any one of Formulae I, III-a, and III-b are are provided as a pharmaceutical composition or formulation. Accordingly, the invention provides pharmaceutical formulations comprising a compound of any one of Formulae I, III-a, and III-band pharmaceutically acceptable salts, solvates, and mixtures thereof, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
  • Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated.
  • the vehicle can be inert or it can possess pharmaceutical benefits.
  • the amount of vehicle employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Exemplary pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers, such as the TWEENS; wetting agents, such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • Effective concentrations of a compound of any one of Formulae I, III-a,and III-band pharmaceutically acceptable salts, solvates, and mixtures thereof, are mixed with a suitable pharmaceutical acceptable vehicle.
  • methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as TWEEN
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the chosen vehicle.
  • the effective concentration sufficient for ameliorating the symptoms of the disease treated may be empirically determined.
  • Compounds of any one of Formulae I, III-a, and III-b, IV-a and IV-b maybe provided for orally, topically, parenterally, intravenously, by intramuscular injection, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations.
  • Dosage formulations suitable for oral use include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations.
  • oral formulations contain from 0.1 to 99% of a compound of any one of Formulae I, III-a, and III-b.
  • oral formulations contain at least 5% (weight %) of a compound of Formula I.
  • Some embodiments contain from 25% to 50% or from 5% to 75 % of a compound of any one of Formulae I, III-a, and III-b.
  • Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like.
  • the pharmaceutically acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Oral formulations may contain preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, taste-masking agents, and coloring agents.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, or sucrose.
  • Such formulations may also contain a demulcent.
  • Compounds of any one of Formulae I, III-a, and III-b can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions syrups, or elixirs, for example. Moreover, formulations containing these chemical entities can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monsoleate, or acacia), non-aqueous vehicles, which can include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats
  • emulsifying agents e.g.
  • typical suspending agents include methylcellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and
  • typical preservatives include methyl paraben and sodium benzoate.
  • Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents; naturally-occurring phosphatides, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan substitute.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
  • Tablets typically comprise conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components often depends on secondary considerations like taste, cost, and shelf stability.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example as a solution in 1,3-butanediol.
  • a non-toxic parentally acceptable vehicle for example as a solution in 1,3-butanediol.
  • the acceptable vehicles that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be useful in the preparation of injectables.
  • Compounds of any one of Formulae I, III-a, and III-b may be provided for parenteral administration in a sterile medium.
  • Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques.
  • Compounds of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the carrier comprises at least 90% by weight of the total composition.
  • the carrier for parenteral administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols.
  • Compounds of any one of Formulae I, III-a, and III-b may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye.
  • Topical compositions may be in any form including, for example, solutions, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, and the like.
  • Such solutions maybe formulated as 0.01%-10% isotonic solutions, pH 5-7, with appropriate salts.
  • Compounds of any one of Formulae I, III-a, and III-b may also be formulated for transdermal administration as a transdermal patch.
  • Topical compositions comprising a compound of any one of Formulae I, III-a, and III-b can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
  • carrier materials such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
  • compositions suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
  • Representative emollient include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetyl
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine and phosphatidylcholines.
  • compositions useful for attaining systemic delivery of the compound include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).
  • a conventional propellant e.g., dichlorodifluoromethane or trichlorofluoromethane.
  • compositions of the present invention may also optionally comprise an activity enhancer.
  • the activity enhancer can be chosen from a wide variety of molecules that function in different ways to enhance or be independent of therapeutic effects of the present compounds.
  • Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers.
  • compositions of the invention may also contain additional active agents that can be chosen from a wide variety of molecules, which can function in different ways to enhance the therapeutic effects of a compound of any one of Formulae I, III-a, and III-b.
  • additional active agents that can be chosen from a wide variety of molecules, which can function in different ways to enhance the therapeutic effects of a compound of any one of Formulae I, III-a, and III-b.
  • These optional other active agents, when present, are typically employed in the compositions of the invention at a level ranging from 0.01% to 15%. Some embodiments contain from 0.1% to 10% by weight of the composition. Other embodiments contain from 0.5% to 5% by weight of the composition.
  • the invention includes packaged pharmaceutical formulations.
  • packaged formulations include a pharmaceutical composition comprising a compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof, and instructions for using the composition to treat a mammal (typically a human patient).
  • the instructions are for using the pharmaceutical composition to treat a patient suffering from a disease responsive to inhibition of Btk activity and/ or inhibition of B-cell and/or myeloid-cell activity.
  • the invention can include providing prescribing information; for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.
  • the invention includes a method of treating a patient, for example, a mammal, such as a human, having a disease responsive to inhibition of Btk activity, comprising administrating to the patient having such a disease, an effective amount of a compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof.
  • compounds of any one of Formulae I, III-a, and III-b may also inhibit other kinases, such that alleviation of disease, disease symptoms, preventative, and prophylactic treatment of conditions associated with these kinases is also within the scope of this invention.
  • Treatment also includes inhibiting Btk activity and/ or inhibiting B-cell and/or myeloid-cell activity, by inhibiting ATP binding or hydrolysis by Btk or by some other mechanism, in vivo , in a patient suffering from a disease responsive to inhibition of Btk activity, wherein compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof can be used.
  • An example of an effective concentration would be that concentration sufficient to inhibit Btk activity in vitro.
  • An effective concentration may be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability.
  • the condition responsive to inhibition of Btk activity and/ or B-cell and/or myeloid-cell activity is cancer, a bone disorder, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory reaction.
  • the invention includes compounds for use in treating a patient having cancer, a bone disorder, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory reaction usingan effective amount of a compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof.
  • the conditions and diseases that can be affected using compounds of any one of Formulae I, III-a, and III-b include, but are not limited to:
  • Btk is a known inhibitor of apoptosis in lymphoma B-cells. Defective apoptosis contributes to the pathogenesis and drug resistance of human leukemias and lymphomas. Described herein is a method of promoting or inducing apoptosis in cells expressing Btk comprising contacting the cell with a compound of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b, pharmaceutically acceptable salts, solvates, and mixtures thereof.
  • the invention provides a compound of any one of Formulae I, III-a, and III-b for use in the treatment of the above mentioned indications, and pharmaceutically acceptable salts, solvates, and mixtures thereof, or a composition (e.g., a pharmaceutical composition thereof), is the only active agent given to a patient and also includes the treatment in which a compound of any one of Formulae I, III-a, and III-b, and pharmaceutically acceptable salts, solvates, and mixtures thereof, or a composition (e.g., a pharmaceutical composition thereof), is provided for the treatment in combination with one or more additional active agents.
  • the additional active agent(s) are for use in a patient sequentially or consecutively with a compound or composition of the present invention.
  • the invention provides the compounds described in the claims for use in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and/or asthma in which a compound of any one of Formulae I, III-a, and III-b, and pharmaceutically acceptable salts, solvates, and mixtures thereof, is the only active agent and also includes the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and/or asthma in which a compound of any one of Formulae I, III-a, and III-b, and pharmaceutically acceptable salts, solvates, and mixtures thereof, are for use in combination with one or more additional active agents.
  • the invention provides compounds of Formulae I, III-a, and III-b for use in treating cancer, a bone disorder, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory reaction, which comprises providing a treatment to a patient in need thereof of an effective amount of a compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof, together with a second active agent, which can be useful for treating a cancer, a bone disorder, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory reaction.
  • the second agent may be an anti-inflammatory agent.
  • Treatment with the second active agent may be prior to, concomitant with, or following treatment with a compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof.
  • a compound of any one of Formulae I, III-a, and III-b and pharmaceutically acceptable salts, solvates, and mixtures thereof is combined with another active agent in a single dosage form.
  • Suitable antitumor therapeutics that may be used in combination with a compound of any one of Formulae I, III-a, and III-b include, but are not limited to, chemotherapeutic agents, for example mitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or a combination comprising at least one of the foregoing chemotherapeutic agents. Radiotherapeutic antitumor agents may also be used, alone or in combination with chemotherapeutic agents.
  • Compounds of any one of Formulae I, III-a, and III-b can be useful as chemosensitizing agents, and, thus, can be useful in combination with other chemotherapeutic drugs, in particular, drugs that induce apoptosis.
  • a method for increasing sensitivity of cancer cells to chemotherapy comprising administering to a patient undergoing chemotherapy a chemotherapeutic agent together with a compound of any one of Formulae I, II-a, II-b, III-a, III-b, IV-a and IV-b and pharmaceutically acceptable salts, solvates, and mixtures thereof, in an amount sufficient to increase the sensitivity of cancer cells to the chemotherapeutic agent is also described herein.
  • chemotherapeutic drugs examples include topoisomerase I inhibitors (camptothesin or topotecan), topoisomerase II inhibitors (e.g. daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g. taxol and vinblastine), biological agents (e.g. antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, and cytokines), tyrosine kinase inhibitors (e.g., Gleevac) and the like.
  • topoisomerase I inhibitors camptothesin or topotecan
  • topoisomerase II inhibitors e.g. daunomycin and etoposide
  • alkylating agents e.g. cyclophosphamide, melphalan and BCNU
  • tubulin directed agents e.g. taxol and vinblastine
  • biological agents e.g. antibodies
  • chemotherapeutic drugs that can be used in combination with the present compounds also include R-CHOP (cyclophosphamide (also called Cytoxan/Neosar), doxorubicin (or Adriamycin), vincristine (Oncovin) and prednisolone), ICE (ifosfamide, carboplatin, and etoposide), DHAP (dexamethasone, cisplatin, and cytarabine), ESHAP (etoposide, methylpredinsolone, cytarabine, and cisplatin), gemcitabine, Rituxan®, Treanda®, chlorambucil, fludarabine, alemtuzumab, and the like.
  • R-CHOP cyclophosphamide
  • doxorubicin or Adriamycin
  • vincristine Oncovin
  • prednisolone prednisolone
  • ICE ifosfamide, carboplatin, and e
  • Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
  • NSAIDs include, but are not limited to ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.
  • NSAIDs also include COX-2 specific inhibitors (i.e., a compound that inhibits COX-2 with an IC 50 that is at least 50-fold lower than the IC 50 for COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.
  • COX-2 specific inhibitors i.e., a compound that inhibits COX-2 with an IC 50 that is at least 50-fold lower than the IC 50 for COX-1
  • celecoxib valdecoxib
  • lumiracoxib etoricoxib
  • etoricoxib etoricoxib
  • rofecoxib rofecoxib
  • the anti-inflammatory agent is a salicylate.
  • Salicylates include but are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
  • the anti-inflammatory agent may also be a corticosteroid.
  • the corticosteroid may be chosen from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
  • the anti-inflammatory therapeutic agent is a gold compound such as gold sodium thiomalate or auranofin.
  • the invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.
  • a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.
  • the second anti-inflammatory agent that may be used in combination with any one or more compounds of the present invention includes biologics and oral agents for treating rheumatoid arthritis.
  • At least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, infliximab, and adalimumab (Humira®) which are anti-TNF alpha monoclonal antibodies.
  • an anti-C5 monoclonal antibody such as eculizumab or pexelizumab
  • TNF antagonist such as entanercept, infliximab, and adalimumab (Humira®) which are anti-TNF alpha monoclonal antibodies.
  • Still other embodiments of the invention pertain to combinations in which at least one active agent is an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.
  • an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.
  • Still other embodiments of the invention pertain to combinations with Rituxan® (Rituximab) or other agents that work by selectively depleting CD20+ B-cells.
  • Dosage levels of the order for example, of from 0.1 mg to 140 mg per kilogram of body weight per day can be useful in the treatment of the above-indicated conditions (0.5 mg to 7 g per patient per day).
  • the amount of active ingredient that may be combined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain from 1 mg to 500 mg of an active ingredient.
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated. In some embodiments, for example, for the treatment of an allergic disorder and/or autoimmune and/or inflammatory disease, a dosage regimen of 4 times daily or less is used. In some embodiments, a dosage regimen of 1 or 2 times daily is used. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy.
  • a labeled form of a compound of the invention can be used as a diagnostic for identifying and/or obtaining compounds that have the function of modulating an activity of a kinase as described herein.
  • the compounds of the invention may additionally be used for validating, optimizing, and standardizing bioassays.
  • label herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc.
  • Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc.
  • the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above.
  • the label can directly or indirectly provide a detectable signal.
  • the cooled mixture was diluted with ethyl acetate and water, filtered, separated, the ethyl acetate layer extracted 1X with ethyl acetate, the combined ethyl acetate layers washed with brine 4X, dried over Na 2 SO 4 , filtered and concentrated.
  • the product was purified by column chromatography (silica) CH 2 Cl 2 /MeOH to give 3 .
  • reaction was cooled to -5 °C using an ice/acetone bath, water (70 mL) and 4N hydrochloric acid (70 mL) was added and the reaction was stirred at reflux for 1 h in order to destroy the borane complex with pyrazole.
  • the reaction was cooled to room temperature and concentrated under reduced pressure to a volume of approximately 30 mL.
  • Ethyl acetate (175 mL) was added and the mixture stirred for 15 min. The aqueous layer was separated and extracted with ethyl acetate (4 ⁇ 200 mL).
  • a 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (4.00 g, 2.20 mmol) in ethanol (160 mL).
  • the bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle.
  • Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521.
  • reaction mixture was poured in to a 1:1 mixture of ice/water (500 mL), diluted with 95:5 hexanes/methylene chloride (250 mL) and the layers were separated.
  • the aqueous layer was extracted with hexanes (100 mL) and the combined organic layers were washed with water (2 ⁇ 100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) and dried over sodium sulfate.
  • the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the crude product was suspended in hexanes (40 mL) and heated until dissolved. The solution was evaporated to a volume to 20 mL and allowed to cool to room temperature overnight.
  • dichloro 1,1'-bis(diphenylphosphino) ferrocene palladium (II) dichloromethane adduct 800 mg, 0.98 mmol was added, and the reaction mixture was heated to 100 °C for 6 h. After this time, the reaction was cooled to room temperature, and water (50 mL) was added. The aqueous layer was extracted with with ethyl acetate (2 x 25 mL).
  • a microwave tube equipped with a magnetic stirrer was charged with 6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrazin-2-ylamino)pyridazin-3(2 H )-one (225 mg, 0.80 mmol), N-(6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (463 mg, 1.13 mmol), DME (5 mL) and 1M aqueous sodium carbonate (2 mL).
  • a master mix minus Btk enzyme is prepared containing 1X Cell Signaling kinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 mM dithiothreitol, 0.1 mM Na 3 VO 4 , 10 mM MgCl 2 ), 0.5 ⁇ M Promega PTK Biotinylated peptide substrate 2, and 0.01% BSA.
  • a master mix plus Btk enzyme is prepared containing 1X Cell Signaling kinase buffer, 0.5 ⁇ M PTK Biotinylated peptide substrate 2, 0.01% BSA, and 100 ng/well (0.06 mU/well) Btk enzyme.
  • Btk enzyme is prepared as follows: full length human wildtype Btk (accession number NM-000061) with a C-terminal V5 and 6x His tag was subcloned into pFastBac vector for making baculovirus carrying this epitope-tagged Btk.
  • Generation of baculovirus is done based on Invitrogen's instructions detailed in its published protocol "Bac-toBac Baculovirus Expression Systems" (Cat. Nos. 10359-016 and 10608-016).
  • Passage 3 virus is used to infect Sf9 cells to overexpress the recombinant Btk protein.
  • the Btk protein is then purified to homogeneity using Ni-NTA column.
  • the purity of the final protein preparation is greater than 95% based on the sensitive Sypro-Ruby staining.
  • a solution of 200 ⁇ M ATP is prepared in water and adjusted to pH7.4 with 1N NaOH.
  • a quantity of 1.25 ⁇ L of compounds in 5%DMSO is transferred to a 96-well 1 ⁇ 2 area Costar polystyrene plate. Compounds are tested singly and with an 11-point dose-responsive curve (starting concentration is 10 ⁇ M; 1:2 dilution).
  • a quantity of 18.75 ⁇ L of master mix minus enzyme (as a negative control) and master mix plus enzyme is transferred to appropriate wells in 96-well 1 ⁇ 2 area costar polystyrene plate.
  • the Lanthascreen assay can be used to evaluate Btk activity through quantification of its phosphorylated peptide product.
  • the FRET that occurs between the fluorescein on the peptide product and the terbium on the detection antibody decreases with the addition of inhibitors of Btk that reduce the phosphorylation of the peptide.
  • Btk (h) (0.1 ng/25 ul reaction) is incubated with 50 mM Hepes pH 7.5, 10 mM MgCl2, 2 mM MnCl 2 , 2 mM DTT, 0.2 mM NaVO4, 0.01% BSA, and 0.4 uM fluorescein poly-GAT.
  • the reaction is initiated by the addition of ATP to 25 uM (Km of ATP). After incubation for 60 minutes at room termperature, the reaction is stopped by the addition of a final concentration of 2 nM Tb-PY20 detection antibody in 60 mM EDTA for 30 minutes at room temperature. Detection is determined on a Perkin Elmer Envision with 340nM excitation and emission at 495 and 520nm.
  • Ramos cells are incubated at a density of 0.5x10 7 cells/ml in the presence of test compound for 1 hr at 37 °C. Cells are then stimulated by incubating with 10 ⁇ g/ml antihuman IgM F(ab) 2 for 5 minutes at 37 °C. Cells are pelleted, lysed, and a protein assay is performed on the cleared lysate. Equal protein amounts of each sample are subject to SDS-PAGE and western blotting with either anti-phosphoBtk(Tyr223) antibody (Cell Signaling Technology #3531; Epitomics, cat.
  • B-cells are purified from spleens of 8-16 week old Balb/c mice using a B-cell isolation kit (Miltenyi Biotech, Cat # 130-090-862). Testing compounds are diluted in 0.25% DMSO and incubated with 2.5 x 10 5 purified mouse splenic B-cells for 30 min prior to addition of 10 ⁇ g/ml of an anti-mouse IgM antibody (Southern Biotechnology Associates Cat # 1022-01) in a final volume of 100 ⁇ l.
  • B-cell isolation kit Miltenyi Biotech, Cat # 130-090-862
  • Testing compounds are diluted in 0.25% DMSO and incubated with 2.5 x 10 5 purified mouse splenic B-cells for 30 min prior to addition of 10 ⁇ g/ml of an anti-mouse IgM antibody (Southern Biotechnology Associates Cat # 1022-01) in a final volume of 100 ⁇ l.
  • T cells are purified from spleens of 8-16 week old Balb/c mice using a Pan T cell isolation kit (Miltenyi Biotech, Cat # 130-090-861). Testing compounds are diluted in 0.25% DMSO and incubated with 2.5 x 10 5 purified mouse splenic T cells in a final volume of 100 ⁇ l in flat clear bottom plates precoated for 90 min at 37°C with 10 ⁇ g/ml each of anti-CD3 (BD # 553057) and anti-CD28 (BD # 553294) antibodies.
  • Total mouse splenocytes are purified from spleens of 8-16 week old Balb/c mice by red blood cell lysis (BD Pharmingen #555899). Testing compounds are diluted to 0.5% DMSO and incubated with 1.25 x 10 6 splenocytes in a final volume of 200 ⁇ l in flat clear bottom plates (Falcon 353072) for 60 min at 37°C. Cells are then stimulated with the addition of 15 ⁇ g/ml IgM (Jackson ImmunoResearch 115-006-020), and incubated for 24 hr at 37°C, 5% CO 2 .
  • cells are transferred to conical bottom clear 96-well plates and pelleted by centrifugation at 1200 x g x 5 min.
  • Cells are preblocked by CD16/CD32 (BD Pharmingen #553142), followed by triple staining with CD19-FITC (BD Pharmingen #553785), CD86-PE (BD Pharmingen #553692), and 7AAD (BD Pharmingen #51-68981E).
  • Cells are sorted on a BD FACSCalibur and gated on the CD19 + /7AAD - population. The levels of CD86 surface expression on the gated population is measured versus test compound concentration.
  • the following is a procedure for a standard B-ALL cell survival study using an XTT readout to measure the number of viable cells.
  • This assay can be used to test compounds disclosed in this application for their ability to inhibit the survival of B-ALL cells in culture.
  • One human B-cell acute lymphoblastic leukemia line that can be used is SUP-B15, a human Pre-B-cell ALL line that is available from the ATCC.
  • SUP-B15 pre-B-ALL cells are plated in multiple 96-well microtiter plates in 100 ⁇ l of Iscove's media + 20% FBS at a concentration of 5 x 10 5 cells/ml. Test compounds are then added with a final conc. of 0.4% DMSO. Cells are incubated at 37°C with 5% CO 2 for up to 3 days. After 3 days cells are split 1:3 into fresh 96-well plates containing the test compound and allowed to grow up to an additional 3 days. After each 24h period, 50 ul of an XTT solution (Roche) is added to one of the replicate 96-well plates and absorbance readings are taken at 2, 4 and 20 hours following manufacturer's directions. The reading taken with an OD for DMSO only treated cells within the linear range of the assay (0.5- 1.5) is then taken and the percentage of viable cells in the compound treated wells are measured versus the DMSO only treated cells.
  • Examples 1-3 and 11-16 above are tested in the Btk biochemical assay described herein (Example 4) and all of the compounds of Formula I disclosed in Examples 1-3 and 11-16 above exhibit an IC 50 value less than or equal to 2 micromolar and certain of those compounds exhibit an IC 50 value less than or equal to 1 micromolar. Certain of those compounds exhibit an IC 50 value less than or equal to 25 nM. Certain of those compounds exhibit an IC 50 value less than or equal to 10 nM. Certain of those compounds exhibit an IC 50 value less than or equal to 5 nM.
  • Some of the compounds disclosed herein are tested in an assay for inhibition of B cell activity (under the conditions described in Example 8), and exhibit an IC 50 value less than or equal to 10 micromolar. Certain of those compounds exhibit an IC 50 value less than or equal to 0.5 micromolar. Certain of those compounds exhibit an IC 50 value less than or equal to 100 nM in this assay.
  • Some of the compounds disclosed herein exhibit both biochemical and cell-based activity. For example, some of the compounds disclosed herein exhibit an IC 50 value less than or equal to 1 micromolar in the Btk biochemical assay described herein (Example 4) and an IC 50 value less than or equal to 10 micromolar in at least one of the cell-based assays (other than the T-cell assay) described herein (Examples 5, 6, 8 or 9).
  • Certain of those compounds exhibit an IC 50 value less than or equal to 50 nM in the Btk biochemical assay described herein (Example 4) and an IC 50 value less than or equal to 500 nM in at least one of the cell-based assays (other than the T-cell assay) described herein (Examples 5, 6, 8 or 9). Certain of those compounds exhibit an IC 50 value less than or equal to 10 nM and an IC 50 value less than or equal to 100 nM in at least one of the cell-based assays (other than the T-cell assay) described herein (Examples 5, 6, 8 or 9).
  • reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (2 ⁇ 50 mL). The organic layers were combined, washed with water (50 mL) and brine (50 mL), and dried over sodium sulfate.
  • a 500-mL Parr reactor bottle was purged with nitrogen and charged with 13 (6.92 g, 25.9 mmol), ethyl acetate (150 mL) and 10% palladium on carbon (50% wet, 150 mg dry weight).
  • the bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 2 h. After this time the hydrogen was evacuated and nitrogen charged into the reactor.
  • the catalyst was removed by filtration through a pad of Celite 521 and the filter cake washed with methylene chloride (400 mL).
  • the reaction was cooled to 0 °C using an ice bath, and saturated aqueous sodium bicarbonate (150 mL) was added dropwise. The layers were separated, and aqueous layer was extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure.
  • a 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 180 mg dry weight) and a solution of 21 (1.00 g, 5.10 mmol) in ethanol (100 mL).
  • the bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle.
  • Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521.
  • a 15-mL pressure tube equipped with a magnetic stirrer and screw cap with a septum was charged with 6a (400 mg, 3.09 mmol), 6b (570 mg, 4.63 mmol), potassium phosphate (692 mg, 6.18 mmol), water (1.5 mL), and 1-butanol (6 mL). After bubbling nitrogen through the resulting suspension for 30 min, bis(di- tert -butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (547 mg, 0.77 mmol) was added. The tube was sealed, and the reaction mixture was heated for 16 h in a 130 °C bath.
  • reaction was cooled to 0 °C, and anhydrous pyridine (2.63 g, 33.3 mmol) was added. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 16 h. After this time, the solvents were removed under reduced pressure, and the resulting residue was partitioned between water (100 mL) and methylene chloride (200 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2 ⁇ 200 mL). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • a 15-mL pressure tube equipped with a magnetic stirrer and screw cap with a septum was charged with 6e (90 mg, 0.30 mmol), 6f (156 mg, 0.39 mmol), sodium carbonate (95 mg, 0.90 mmol), water (0.5 mL), 1,4-dioxane (1.8 mL), and DMF (0.9 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) was added; the tube was sealed, and the reaction mixture was heated for 16 h in a 120 °C bath.
  • reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (100 ml) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was evaporated under reduced pressure.
  • Tetrakis(triphenylphosphine)palladium (175 mg, 0.151 mmol) was added and the mixture was refluxed at 125 °C (bath temperature) for 14 h. The reaction mixture was then cooled to room temperature, and water (100 mL) was added. The resulting precipitate was filtered, and the filter cake was washed with water (250 mL).
  • a 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 100 mg dry weight) and a solution of 2c (500 mg, 1.55 mmol) in ethanol (20 mL).
  • the bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 4 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle.
  • Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521.
  • Tetrakis(triphenylphosphine)palladium (66 mg, 0.057 mmol) was added and the mixture was stirred at 100 °C (bath temperature) for 4 d. The reaction mixture was then cooled to room temperature, and water (50 mL) was added.
  • a 10-mL single-neck round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 2h (75 mg, 0.129 mmol), methanol (2 mL) and 4 M HCl in dioxane (2 mL) and the mixture stirred for 2 h. After this time, ethyl acetate (20 mL) and water (20 mL) were added. The pH was adjusted to 6.5 with aqueous 10% potassium carbonate. The aqueous layer was separated and extracted with ethyl acetate (2 ⁇ 25 mL). The combined organic layers were washed with brine (20 mL) and dried over sodium sulfate. The drying agent was removed by filtration.
  • a 100-mL pressure flask is equipped with a magnetic stirrer was charged with tert-butyl-N-(piperidin-3-yl)benzamide (130 mg, 0.5 mmol), dioxane (10 mL), 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one (127 mg, 0.5 mmol), and cesium carbonate (326 mg, 1 mmol). Argon is bubbled through the solution whilst sonicating for 15 min.
  • Tris (dibenzylideneacetone) dipalladium (0) (46 mg, 0.05 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (66 mg, 0.1 mmol) were then added, the flask was sealed and heated to 120 °C for 8 h.

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Claims (16)

  1. Composé de formule I, ou l'un de ses sels pharmaceutiquement acceptables, solvates ou mélanges, dans lequel
    Figure imgb0673
    V représente 0 ou NH ;
    R1 représente:
    Figure imgb0674
    Figure imgb0675
    Figure imgb0676
    Figure imgb0677
    Figure imgb0678
    Figure imgb0679
    Figure imgb0680
    Figure imgb0681
    Figure imgb0682
    Figure imgb0683
    Figure imgb0684
    Figure imgb0685
    Figure imgb0686
    Figure imgb0687
    Figure imgb0688
    Figure imgb0689
    Figure imgb0690
    Figure imgb0691
    R2 représente H, un groupe OH, ou alkyle en C1 à C3 éventuellement substitué par un groupe OH ou N(R10)2 ;
    le cycle A représente
    Figure imgb0692
     dans lesquels * indique le point de fixation au radical R1CON (R2)- et ** indique le point de fixation au cycle pyridazinonyle ;
    R3 représente H, CH3 ou CF3 ;
    le cycle B représente
    Figure imgb0693
    Figure imgb0694
    Figure imgb0695
     ou
    Figure imgb0696
     éventuellement substitué par 1 à 3 radicaux R4 ;
    chaque R4 représente indépendamment H, un groupe - Ra, -ORb, -SRb, -NRbRc, halogéno, cyano, nitro, -CORb, - CO2Rb, -CONRbRc, -OCORb, -OCO2Ra, -OCONRbRc, -NRcCORb, - NRcCO2Ra, -NRcCONRbRc, -CO2Rb, -CONRbRc, -NRcCORb, -SORa, - SO2Ra, -SO2NRbRc, ou -NRcSO2Ra ; ou deux groupes R4 adjacents sont éventuellement pris ensemble pour former un cycle de 5 ou 6 chaînons comportant 0 à 2 hétéroatomes choisis parmi 0, S ou N, dans lequel ledit cycle de 5 ou 6 chaînons est fusionné au cycle B ;
    Ra représente un groupe alkyle en C1 à C6, cycloalkyle, hétérocycloalkyle, aryle, ou hétéroaryle, dans lequel chaque membre de Ra est éventuellement substitué par un à trois groupes R11 ;
    Rb représente H, un groupe alkyle en C1 à C6, cycloalkyle, hétérocycloalkyle, aryle, ou hétéroaryle, dans lequel chaque membre de Rb sauf H est éventuellement substitué par un à trois groupes R 11 ;
    Rc représente H ou un groupe alkyle en C1 à C4 éventuellement substitué par un à trois groupes R11 ; ou Rb et Rc, et l'atome d'azote auquel ils sont fixés, forment un groupe hétérocycloalkyle éventuellement substitué ;
    chaque R11 est choisi indépendamment parmi des groupes alkyle en C1 à C4, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, arylalkyl en C1 à C4-, hétéroarylalkyl en C1 à C4-, cycloalkylalkyl en C1 à C4-, hétérocycloalkylalkyl en C1 à C4-, halogénoalkyl en C1 à C4-, -O-alkyle en C1 à C4, -O-hétérocycloalkyle, -O-alkyl en C1 à C4-phényle, -alkyl en C1 à C4-OH, -O-halogénoalkyle en C1 à C4, halogéno,-OH, -NH2, -alkyl en C1 à C4-NH2, -NH(alkyle en C1 à C4), -N(alkyl en C1 à C4) (alkyle en C1 à C4) , -N(alkyl en C1 à C4) (alkyl en C1 à C4-phényle), -NH (alkyl en C1 à C4-phényle), -NH-hétérocycloalkyle, cyano, nitro, oxo,-CO2H, -C(O)O-alkyle en C1 à C4, -CON(alkyl en C1 à C4)-(alkyle en C1 à C4), -CONH(alkyle en C1 à C4), -CONH2,-NHC(O) (alkyle en C1 à C4) , -NHC(O) (phényle), -N(alkyl en C1 à C4) C(O) (alkyle en C1 à C4) , -N (alkyl en C1 à C4)-C(O)(phényle), -C (O)-alkyle en C1 à C4, -C(O)-en C1 à C4-phényle, -C(O)-halogénoalkyle en C1 à C4, -OC(O)-alkyle en C1 à C4, -SO2(alkyle en C1 à C4) ,-SO2(phényle), -SO2(halogénoalkyle en C1 à C4), -SO2NH2,-SO2NH(alkyle en C1 à C4), -SO2NH(phényle), -NHSO2(alkyle en C1 à C4), -NHSO2(phényle), et -NHSO2 (halogénoalkyle en C1 à C4), dans lequel lesdits groupes alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, phényle et halogénoalkyle sont éventuellement substitués indépendamment par un à trois groupes R12;
    chaque R12 est choisi indépendamment parmi des groupes alkyle en C1 à C4, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, arylalkyl en C1 à C4-, hétéroarylalkyl en C1 à C4-, cycloalkylalkyl en C1 à C4-, hétérocycloalkylalkyl en C1 à C4-, halogénoalkyl en C1 à C4-, -O-alkyle en C1 à C4, -O-hétérocycloalkyle, -O-alkyl en C1 à C4-phényle, -alkyl en C1 à C4-OH, -O-halogénoalkyle en C1 à C4, halogéno, - OH, -NH2, -alkyl en C1 à C4-NH2, -NH(alkyle en C1 à C4) , -N(alkylen C1 à C4) (alkyle en C1 à C4), -N(alkylen C1 à C4) (alkyl en C1 à C4-phényle), -NH (alkyl en C1 à C4-phényle), -O-hétérocycloalkyle, cyano, nitro, oxo,-CO2H, -C(O)O-alkyle en C1 à C4, -CON(alkyl en C1 à C4)-(alkyle en C1 à C4), -CONH(alkyle en C1 à C4), -CONH2,-NHC(O) (alkyle en C1 à C4), -NHC(O) (phényle), -N(alkyl en C1 à C4)C(O) (alkyle en C1 à C4), -N(alkyl en C1 à C4)-C(O) (phényle), -C(O)-alkyle en C1 à C4, -C(O)-en C1 à C4-phényle, -C(O)-halogénoalkyle en C1 à C4, -OC(O)-alkyle en C1 à C4, -SO2(alkyle en C1 à C4),-SO2(phényle), -SO2(halogénoalkyle en C1 à C4), -SO2NH2,-SO2NH(alkyle en C1 à C4), -SO2NH(phényle), -NHSO2 (alkyle en C1 à C4), -NHSO2(phényle), et -NHSO2 (halogénoalkyle en C1 à C4) ;
    X représente N ou CR6 ;
    Y représente N ou CR7 ;
    Z représente N ou CR8 ; à condition qu'un seul de X, Y et Z représente N à la fois ;
    R5 représente H ou F ;
    R6 représente H, CH3, F, Cl, CN, OCH3, OH, CF3, CH2OH, CH2F, CH=O, CH2OCH3, COCH3, ou (CH2)2OH ;
    R7 représente H, CH3, F, Cl, CN ou OCH3 ;
    R8 représente H, CH3, CF3, F, Cl, CN ou OCH3 ;
    W représente CH ou N ;
    W' représente CH ou N ;
    chaque R9 représente indépendamment un groupe alkyle en C1 à C3 ;
    chaque R10 représente indépendamment H ou CH3 ;
    chaque R13 représente indépendamment H, un groupe halogéno, alkyle en C1 à C6, alcoxy en C1 à C6, ou halogénoalkyle en C1 à C6 ;
    chaque R14 représente indépendamment H, un groupe C(=O)H, C(=O)R9, ou alkyle en C1 à C6 dans lequel ledit groupe alkyle est éventuellement substitué par un ou plusieurs groupes OH ;
    R15 représente CH3, F, Cl, Br, OH, ou OCH3 ;
    R16 représente F, Cl, Br, CH3, ou CF3 ;
    R17 représente F ou OCH3 ;
    R18 représente F ou Cl ; et
    R19 représente F ou CH3.
  2. Composé selon la revendication 1 dans lequel le cycle A représente :
    Figure imgb0697
     dans lequel X, Y et Z peuvent représenter indépendamment N ou X peut représenter CR6, Y peut représenter CR7 et/ou Z peut représenter CR8.
  3. Composé selon la revendication 2, où le composé représente soit
    Figure imgb0698
     soit
    Figure imgb0699
  4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel R5 représente H ou F et/ou R1 représente :
    Figure imgb0700
    Figure imgb0701
    Figure imgb0702
    Figure imgb0703
     ou
    Figure imgb0704
  5. Composés selon l'une quelconque des revendications 1 à 4,
    dans lesquels X = CR6, R6 représente H, CH3, F, Cl, CH2OH, CH2F, CH=O, CH2OCH3, ou (CH2)2OH, et/ou
    dans lesquels Y = CR7, R7 représente H, F ou CH3, et/ou
    dans lesquels Z = CR8, R8 représente H.
  6. Composé selon l'une quelconque des revendications 1 à 5,
    dans lequel R2 représente H, CH3, ou CH2OH, et/ou
    dans lequel le cycle B représente soit un groupe hétéroaryle de 5 ou 6 chaînons comportant au moins un atome de cycle d'azote en position 2, et peut représenter, par exemple,
    un groupe pyrazolyle, oxazolyle, pyrimidinyle, pyridinyle, pyridazinyle, pyrazinyle, imidazolyle, ou thiazolyle, ou
    représente un groupe hétérocycloalkyle de 6 chaînons comportant au moins un atome de cycle d'azote, et peut représenter, par exemple, un groupe pipéridinyle, ou
    représente un groupe hétérocycloalkyle de 8 à 10 chaînons comportant au moins un atome de cycle d'azote en position 2.
  7. Composé selon l'une quelconque des revendications 1 à 6, dans lequel R4 représente H, -Ra, -NRbRc, ORb, ou CORb, et/ou
    dans lequel Ra représente un groupe alkyle en C1 à C6, cycloalkyle, ou hétérocycloalkyle, dans lequel lesdits groupes alkyle, cycloalkyle ou hétérocycloalkyle sont éventuellement substitués par un à trois groupes R11 choisis parmi des groupes alkyle en C1 à C4, -OH, hétérocycloalkyle (éventuellement substitué par un à trois groupes R12), -O-alkyle en C1 à C4, -O-hétérocycloalkyle, oxo, halogéno, -NH2, - NH(alkyle en C1 à C4 éventuellement substitué par un à trois groupes R12), -N (alkyle en C1 à C4 éventuellement substitué par un à trois groupes R12)2, et -NH-hétérocycloalkyle, et/ou
    dans lequel Rb représente H, un groupe hétérocycloalkyle, ou alkyle en C1 à C6 éventuellement substitué par un à trois groupes R11 et Rc représente H ou un groupe alkyle en C1 à C4.
  8. Composé selon l'une quelconque des revendications 1 à 6, dans lequel le cycle B avec (R4)1-3 représente :
    Figure imgb0705
     dans lequel R4 représente H, CH3 ou CD3.
  9. Composé selon l'une quelconque des revendications 1 à 6, dans lequel R4 représente H, un groupe CH3, CH2CH3, t-butyle, CF3, -C(OH) (CH3)2, -CH(OH)CH3, - CH2NH(CH2)2OH, -CH2NH(CH2)F, -CH2NHCH3, -CH2N(CH3)2, - CH2NHCH2CF3, -CH2OH, -CH2NH2, -OCH3, NH2, - N(CH3)(CH2)2NMe2, -N(CH3)(CH2)2OH, -N(CH3)(CH2)2NH2, - CH(OH)C(O)N(CH3)2, -C(O)C(O)N(CH3)2, -CH2CHF2, -(CH2)2F, - (CH2)3F, -O(CH2)2N(CH3)2, -C(CH3)OHCF3,
    Figure imgb0706
    Figure imgb0707
    Figure imgb0708
    Figure imgb0709
    Figure imgb0710
    Figure imgb0711
    Figure imgb0712
  10. Composé selon la revendication 1 choisi parmi :
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    5-tert-butyl-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyrazine-2-carboxamide ;
    5-tert-butyl-N-[2-fluoro-5-(6-oxo-5-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylamino}-1,6-dihydropyridazin-3-yl)phényl]pyrazine-2-carboxamide ;
    N-[2-fluoro-5-(6-oxo-5-{4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-ylamino}-1,6-dihydropyridazin-3-yl)-phényl]-1-benzothiophène-2-carboxamide ;
    5-tert-butyl-N-{2-fluoro-5-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyrazine-2-carboxamide ;
    N-[2-fluoro-5-(1-méthyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydro-pyridazin-3-yl)phényl]-1-benzothiophène-2-carboxamide ;
    5-tert-butyl-N-[2-fluoro-5-(1-méthyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydropyridazin-3-yl)phényl]pyrazine-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-benzothiophène-2-carboxamide ;
    5-tert-butyl-N-[2-fluoro-5-(6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydro-pyridazin-3-yl)phényl]pyrazine-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}--5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-(1-hydroxy-2-méthylpropan-2-yl)-benzamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-hydroxy-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-hydroxy-4,5,6,7-tétrahydro-1-benzo-thiophène-2-carboxamide ;
    4-tert-butyl-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}benzamide ;
    N-{2-fluoro-5-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-6-(2-hydroxypropan-2-yl)-pyridine-3-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihriropyridazin-3-yl]phényl}-1H-indole-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-dihydropyridazin-3-yl]phényl}-5-hydroxy-4,5,6,7-tétrahydro-1-benzo-thiophène-2-carboxamide ;
    N-[2-fluoro-5-(6-oxo-5-{4H,6H,7H-pyrazolo-[3,2-c][1,4]oxazin-2-ylamino}-1-,6-dihydropyridazin-3-yl)phényl]-1-benzothiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-(2-hydroxypropan-2-yl)benzamide ;
    5-tert-butyl-N-{2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyrazine-2-carboxamide ;
    4-(1-amino-2-méthylpropan-2-yl)-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-benzamide ;
    (5S)-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-5-hydroxy-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    N-{2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-5,6,7,8-tétrahydroindolizine-2-carboxamide ;
    5-tert-butyl-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyridine-2-carboxamide ;
    4-tert-butyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pipéridin-3-yl]benzamide ;
    (4S)-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5,a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4-hydroxy-4H,5H,6H-cyclopenta-[b]thiophiène-2-carboxamide ;
    (4R)-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4-hydroxy-4H,5H,6H-cyclopenta-[b]thiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-méthoxy-1-benzothiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5,a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-5,6,7,8-tétrahydronaphtalène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-(propan-2-yl)benzamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    5-hydroxy-N-{2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4,5,6,7-tetxahydro-1-benzo-thiophène-2-carboxamide ;
    N-{2,6-difluoro-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    N-{2-méthyl-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    5-tert-hutyl-N-{2-méthyl-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyrazine-2-carboxamide ;
    N-{2,6-diméthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    N-[2-fluoro-5-(6-oxo-5-{4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-ylamino}-1,6-dihydropyridazin-3-yl)-phényl]-4-hydroxy-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    N-{5-[5-({5-cyclopropyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]-2-fluorophényl}-1-benzothiophène-2-carboxamide ;
    N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]pipéridin-3-yl]-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    4-tert-butyl-N-[(3R)-1-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]pipéridin-3-yl]benzamide ;
    4-tert-butyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pyrrolidin-3-yl]benzamide ;
    N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]pipéridin-3-yl]-1-benzothiophène-2-carboxamide ;
    N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)6-oxo-1,6-dihydro-pyridazin-3-yl]pipéridin-3-yl]-4,5,6,7-tétrahydro-1H-indole-2-carboxamide ;
    N-[2-fluoro-5-(6-oxo-5-{4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-ylamino}-1,6-dihydropyridazin-3-yl)-phényl]-4-hydroxy-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    N-[2-fluoro-5-(5-{[5-(2-hydroxyéthyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yllamino}-6-oxo-1,6-dihydro-pyridazin-3-yl)phényl]-1-benzothiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-(1-méthoxy-2-méthylpropan-2-yl)-benzamide ;
    5-tert-butyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pipéridin-3-yl]pyrazine-2-carboxamide ;
    N-{3-[5-({5-cyclopropyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]-6-fluoro-2-méthylphényl}-1-benzothiophène-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-(trifluorométhyl)benzamide ;
    5-tert-butyl-N-{2,6-diméthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyrazine-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}indolizine-2-carboxamide ;
    N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]pipéridin-3-yl]-5,6,7,8-tétrahydro-indolizine-2-carboxamide ;
    N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-3,3-diméthyl-2,3-dihydro-1-benzofurane-6-carboxamide ;
    4-(1-hydroxy-2-méthylpropan-2-yl)-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pipéridin-3-yl]benzamide ;
    N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]pipéridin-3-yl]-4-(1-méthylcyclopropyl)-benzamide ;
    N-6-{fluoro-2-méthyl-3-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    5-tert-butyl-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1,3-thiazole-2-carboxamide ;
    N-{2-fluoro-6-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    N-[6-fluoro-3-(5-{[5-(2-hydroxyéthyl)-4H,5H,6H,7H-pyrazalo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-méthylphényl]-1-benzothiophène-2-carboxamide ;
    4-tert-butyl-N-{1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]azépan-3-yl}benzamide ;
    N-[2-fluoro-5-(1-méthyl-6-oxo-5-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylamino}-1,6-dihydropyridazin-3-yl)phényl]-5,6,7,8-tétrahydroindolizine-2-carboxamide ;
    N-[2-fluoro-5-(6-oxo-5-{4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-ylamino}-1,6-dihydropyridazin-3-yl)-phényl]-5,6,7,8-tétrahydroindolizine-2-carboxamide ;
    N-{5-[5-({5-acétyl-4H,5H,6H,7H-pyrazolo[1,5-a]-pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]-2-fluorophényl}-1-benzothiophène-2-carboxamide ;
    N-{3-fluoro-6-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]pyridin-2-yl}-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    N-[6-fluoro-2-méthyl-3-(6-oxo-5-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylarnino}-1,6-dihydro-pyridazin-3-yl)phényl]-1-benzothiophène-2-carboxamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-5-oxo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    4-hydroxy-N-(2-(hydroxyméthyl)-3-(5-(5-méthyl-4,5,6,7-tétrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phényl)-5,5-diméthyl-5,6-dihydro-4H-cyclopenta[b]thiophène-2-carboxamide ;
    5-tert-butyl-N-(2-(hydroxyméthyl)-3-(5-(5-méthyl-4,5,6,7-tétrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phényl)pyrazine-2-carboxamide ;
    4-hydroxy-N-(2-(hydroxyméthyl)-3-(5-(5-méthyl-4,5,6,7-tétrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phényl)-5,6-dihydro-4H-cyclopenta[b]thiophène-2-carboxamide.
  11. Composé selon la revendication 1 choisi parmi :
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    N-[6-fluoro-3-(5-{[5-(3-fluoropropyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-méthylphényl]-1-benzothiophène-2-carboxamide ;
    N-{3-méthyl-6-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pyridin-2-yl}-1-benzothiophène-2-carboxamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4,5,6,7-tétrahydro-1-benzo-thiophène-2-carboxamide;
    (4S)-N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    (4R)-N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    5-tert-butyl-N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyrazine-2-carboxamide ;
    4-tert-butyl-N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}benzamide ;
    4,4-difluoro-N-{fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    N-[2-fluoro-6-méthyl-3-(6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydro-pyridazin-3-yl)phényl]-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    4-tert-butyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]azépan-3-yl]benzamide ;
    N-[6-fluoro-3-(5-{[5-(2-fluoroéthyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-méthylphényl]-1-benzothiophène-2-carboxamide ;
    N-[3-(5-{[5-(2,2-difluoroéthyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydro-pyridazin-3-yl)-6-fluoro-2-méthylphényl]-1-benzo-thiophène-2-carboxamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-N-méthyl-1-benzothiophène-2-carboxamide ;
    5-tert-butyl-N-{2,6-diméthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}pyridine-2-carboxamide ;
    N-{2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-2,3-dihydro-1H-isoindole-2-carboxamide ;
    N-{3-fluoro-6-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo-[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pyridin-2-yl}-1-benzothiophène-2-carboxamide ;
    N-[3-(5-{[5-(2,2-difluoroéthyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydro-pyridazin-3-yl)-2-fluoro-6-méthylphényl]-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    (4S,5R)-N-{2-fluoro-5-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4,5-dihydroxy-4,5,6,7-tétrahydro-1-benzothiophène-2-carboxamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazépin-2-yl}-amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-1-benzothiophène-2-carboxamide ;
    N-[2-(hydroxyméthyl)-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl]-1-benzothiophène-2-carboxamide ;
    (4R)-N-[2-fluoro-6-méthyl-3-(6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydro-pyridazin-3-yl)phényl]-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    (4S)-N-[2-fluoro-6-méthyl-3-(6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydro-pyridazin-3-yl)phényl]-4-hydroxy-5,5-diméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    3-(tert-butoxy)-N-{2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}azétidine-1-carboxamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-7-hydroxy-3-thiatricyclo-[6.2.1.0^{2,6}]undéca-2(6),4-diène-4-carboxamide ;
    N-{6-fluoro-3-[1-(hydroxyméthyl)-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1.6-dihydropyridazin-3-yl]-2-méthylphényl}-1-benzo-thiophène-2-carboxamide ;
    4-hydroxy-5,5-dimetbyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]pipéridin-3-yl]-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    4-tert-butyl-N-{5-méthyl-2-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]-1,3-thiazol-4-yl}benzamide ;
    N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydro-pyridazin-3-yl]phényl}-4-hydroxy-4,5,5-triméthyl-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    N-{5-[5-({5,5-dioxo-4H,6H,7H-pyrazolo[3,2-c][1,4]-thiazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]-2-fluorophényl}-1-benzothiophène-2-carboxamide ;
    (7R)-N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-7-hydroxy-3-thiatricyclo[6.2.1.0^{2,6}]undéca-2(6),4-diène-4-carboxamide ;
    (7S)-N-{6-fluoro-2-méthyl-3-[5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phényl}-7-hydroxy-3-thiatricyclo[6.2.1.0^{2,6}]undéca-2(6),4-diène-4-carboxamide ;
    (4R)-4-hydroxy-5,5-diméthyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-amino)-6-oxo-1,6-dihydropyridazin-3-yl]pipéridin-3-yl]-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide ;
    (4S)-4-hydroxy-5,5-diméthyl-N-[(3R)-1-[1-méthyl-5-({5-méthyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-amino)-6-oxo-1,6-dihydropyridazin-3-yl]pipéridin-3-yl]-4H,5H,6H-cyclopenta[b]thiophène-2-carboxamide.
  12. Composition pharmaceutique, comprenant un composé selon l'une quelconque des revendications 1 à 11, conjointement avec au moins un véhicule pharmaceutiquement acceptable choisi parmi des supports, des adjuvants, et des excipients,
    où la composition est formulée sous une forme choisie parmi des liquides injectables, des aérosols, des crèmes, des gels, des comprimés, des pilules, des capsules, des sirops, des solutions ophtalmiques, et des patches transdermiques.
  13. Composition pharmaceutique conditionnée, comprenant une composition pharmaceutique selon la revendication 12 ; et
    des instructions pour l'utilisation de la composition afin de traiter un patient souffrant d'une maladie sensible à l'inhibition de l'activité de la Btk.
  14. Composition pharmaceutique selon l'une quelconque des revendications 12 ou 13 comprenant en outre un second agent actif.
  15. Composé selon les revendications 1 à 11 destiné à l'utilisation dans le traitement d'un patient souffrant d'une maladie sensible à l'inhibition de l'activité de la Btk.
  16. Composé destiné à l'utilisation dans le traitement selon la revendication 15, où la maladie comprend des troubles allergiques, y compris mais n'y étant pas limités, l'eczéma, la rhinite allergique ou coryza, le rhume des foins, l'asthme bronchique, l'urticaire et les allergies alimentaires, et d'autres affections atopiques ; des maladies auto-immunes et/ou inflammatoires, y compris mais n'y étant pas limitées, le psoriasis, la maladie de Crohn, le syndrome de l'intestin irritable, la maladie de Sjögren, le rejet de greffe tissulaire, et le rejet hyper-aigu d'organes transplantés, l'asthme, le lupus érythémateux systémique (et la glomérulonéphrite associée), la dermatomyosite, la sclérose en plaques, la sclérodermie, la vascularite (associée aux ANCA et d'autres vascularites), les états hémolytiques et thrombocytopéniques auto-immuns, le syndrome de Goodpasture (et la glomérulonéphrite et l'hémorragie pulmonaire associées), l'athérosclérose, la polyarthrite rhumatoïde, l'arthrose, le purpura thrombocytopénique idiopathique chronique (PTI), la maladie d'Addison, la maladie de Parkinson, la maladie d'Alzheimer, le diabète (type 1), le choc septique, la myasthénie grave, la rectocolite hémorragique, l'anémie aplasique, la maladie coeliaque, la granulomatose de Wegener et d'autres maladies dans lesquelles les cellules et les anticorps proviennent de et sont dirigés contre les propres tissus de l'individu ; des réactions inflammatoires aiguës, y compris mais n'y étant pas limitées, les coups de soleil, la maladie pelvienne inflammatoire, la maladie inflammatoire de l'intestin, l'urétrite, l'uvéite, la sinusite, la pneumonie, l'encéphalite, la méningite, la myocardite, la néphrite, l'ostéomyélite, la myosite, l'hépatite, la gastrite, l'entérite, la dermatite, la gingivite, l'appendicite, la pancréatite, et la cholécystite ; le cancer, y compris mais n'y étant pas limité, des affections malignes, telles que le lymphome à lymphocytes B, et la leucémie lymphoblastique aiguë, la leucémie myélogène aiguë, la leucémie myélogène chronique, la leucémie lymphocytaire chronique et aiguë, la leucémie à trichocytes, la maladie de Hodgkin, le lymphome non-hodgkinien, le myélome multiple, et d'autres maladies qui sont caractérisées par un cancer du sang ou du système lymphatique ; et des troubles osseux, y compris mais n'y étant pas limités, l'ostéoporose.
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